Alphaviruses are a significant cause of human morbidity and mortality with arthropod-borne transmission of these agents resulting in thousands of debilitating infections per annum. Chikungunya virus (CHIKV) is significant public health concern; recently characterized genetic adaptation has allowed this virus to efficiently utilize Aedes albopictus mosquitoes, which are now distributed worldwide, as a primary transmission vector [1,2]. As such, in recent years epidemic transmission of CHIKV has resulted in millions of human infections in Africa, the Indian Ocean islands, India, and Southeast Asia [3-9] as well as the importation of human cases into the United States, the Caribbean, and Europe [8]. In some instances this has been followed by localized transmission cycles [10]. Classical vector control has been the primary strategy to combat mosquito-borne viruses; however, population expansion of mosquito vectors, coupled with a lack of vaccines serves to emphasize the need for the development of alternate anti-viral therapeutic targets. However, interactions between CHIKV and the vertebrate innate immune response that mediate clearance and pathogenesis remain poorly defined. The long-term goal of this research is to use reverse genetics and small animal models of inflammatory arthritis to identify viral and host factors that drive alphavirus-induced disease. The objective of this application is to identify specific interactions between CHIKV envelope glycans and host C-type lectin receptors and elucidate the consequence of those interactions on innate immune cell tropism, signaling, and function. Toward this goal the following specific aims are proposed: Specific Aim 1: To analyze the role of CHIKV N-linked glycans in modulating CHIKV infection and inflammatory gene induction in vivo and in vitro. Specific Aim 2: To identify specific C-type lectin receptors that interact with CHIKV envelope/virion N-linked glycans. We hypothesize that CHIKV pathogenesis is immune mediated and results from stimulation of innate immune activation via interactions between viral N-linked glycans and host C-type lectins. Experiments have been designed to identify specific interactions between a panel of CHIKV deficient for known glycans and an expression library of host C-type lectins. Additionally, these viruses will be evaluated in vitro and in vivo toward characterizing the effects of CHIKV glycans on inflammation, pathogenesis, and innate immune activation and cytokine production. The proposed studies are highly significant to the development of CHIKV anti-viral therapeutics as they will directly assess the interactions between viral and host factors that stimulate protective and pathogenic responses and as such may identify novel therapeutic targets.